Abstract A significant number of HIV+ people are opiate users, and injection drug use and associated risky behaviors contribute to new cases of HIV infection. Antiretroviral therapy (cART) has changed the predominant phenotype of HIV neuropathogenesis from HIV dementia to milder forms of HIV associated neurocognitive disorders (HAND). Opiate abuse increases the severity of HIV brain disease in immunodeficient people and similar effects are expected, but have not been fully defined, for mild HIV brain disease under cART. Because mild HAND is a chronic, life-long dysfunction, therapies are needed both to mitigate mild HAND as well as to limit the potential exacerbating effects of opiates on the disease. We propose to conduct research in vitro and in a mouse model of HIV induced HAND to test our novel hypothesis that buprenorphine, an established opiate medication, may serve such a dual therapeutic purpose. Methadone and buprenorphine are used to treat opiate addiction, but buprenorphine is often preferred due to its safety profile. Buprenorphine also differs from methadone, a full opioid receptor (MOR) agonist, in that it is a partial agonist of MOR and a full antagonist of ? opioid receptors (KOR). Some opioid users treated with buprenorphine show improvement in cognition compared to those on methadone, but the mechanism of improvement is unknown. Studies established that circulating CD14+CD16+ monocytes are infected with HIV and suggested that chemokine mediated transmigration of these infected and uninfected cells across the blood brain barrier (BBB) contributes to HAND through seeding the brain with HIV and mediating chronic neuroinflammation. A recent clinical study showed that the HIV DNA burden in CD14+ monocytes in people on cART predicts severity of their cognitive impairment. Circulating leukocytes, including monocytes, express opioid receptors, and our preliminary data show that human CD14+CD16+ monocytes express MOR and KOR. Using the chemokine CCL2 as a model of inflammation, we also demonstrated that buprenorphine inhibits CCL2-induced adhesion of these cells to brain microvascular endothelium as well as their CCL2-induced chemotaxis. Thus, buprenorphine inhibits important components of CCL2 mediated CD14+CD16+ monocyte transmigration across the BBB. In preclinical studies we showed that buprenophrine inhibits monocyte migration into the brain of EcoHIV infected mice. We also demonstrated that EcoHIV induced cognitive impairment is improved by buprenorphine. A major goal of our proposal is to correlate these 2 findings. Our overall hypothesis is that buprenorphine is a therapeutic that will improve HAND by reducing/inhibiting CCL2 mediated CD14+CD16+ monocyte entry into the CNS, contributing to improved cognitive functions due to decreased neuroinflammation not only in HIV infected opioid abusers, but also in non drug abusing HIV infected people.